The proposed research postulates that gammadelta T cells are involved in triggering the inflammatory process in the rheumatoid arthritis (RA) joint. Preliminary studies in this laboratory have identified a short peptide which is specifically recognized by gammadelta T cell clones previously isolated from RA synovial fluid. The presentation was mediated by DRw53, a DR molecule previously found to be associated with RA-susceptibility. Preliminary studies show that reactivity of T cells to the peptide can be found in the synovial fluid and peripheral blood of patients with early RA. T cells from patients with late RA or from normal individuals do not show such reactivity. In the proposed research these observations will be extended by studying proliferative responses of T cells from a large number of clinically well defined and HLA-typed patients with RA and other arthritic conditions and from normal individuals. Correlations with disease duration, disease activity, and HLA type will be studied. The responding T cell subsets will be characterized by comparing proliferation of purified alphabeta and gammadelta T cells. Limiting dilution analyses will determine the frequency of alphabeta and gammadelta T cell clones which respond to this peptide in the synovial fluid and the peripheral blood. The role of DRw53 and ICAM-1 in presentation of the peptide to gammadelta T cell clones will be studied by using transfectants expressing these molecules. The epitope on DRw53 which mediates the presentation will be delineated by using chimeric DRw53 molecules and by studying presentation by mutated DRw53 molecules and by DRw10, a DR molecule which expresses an epitope cross-reactive with DRw53. The fine specificity of the gammadelta T cells will be determined by using truncated peptides and peptide analogues. Finally experiments will be carried out to design a peptide analogue capable of binding to DRw53 without activating the T cells. This peptide will be studied to assess its inhibitory effect on recognition of the native peptide by the gammadelta T cell clones.